We are requesting funds to obtain an Oxymax Fast System with hardware and treadmills (Columbus Instruments) that would allow multiple users to carry out studies on energy expenditure and fuel utilization in exercising mice. Such measures, which can be performed concurrently on 8 mice, will allow quantitative assessment and comparison of exercise performance in response to a wide variety of parameters including aging, genetic modifications and drug therapy. The PI, Dr. Neil Ruderman, pioneered the use of exercise in the treatment of type 2 diabetes in humans and first demonstrated in rodents that exercise acutely increases insulin sensitivity in skeletal muscle. Most recently, his group has shown that these and other effects of exercise are very likely mediated, in great measure, by the fuel sensing enzyme AMP-activated protein kinase (AMPK). The Ruderman lab will use the Oxymax system with treadmills to examine the acute and chronic effects of exercise on the SIRT1/LKB1/AMPK/eNOS signaling mechanism that it has recently identified in the endothelium of the mouse aorta and is presently studying in other tissues. It will follow up on preliminary data suggesting that this mechanism is activated acutely by exercise and will explore how it and the capacity to exercise are altered in mice with endothelial-cell specific knockdown of SIRT1, eNOS or LKB1. In a collaborative effort with the Ruderman group, Dr. Cohen will determine whether the ability of regular exercise to diminish atherosclerosis in LDLR-/- mice fed a high fat-high sucrose diet is attenuated in mice genetically lacking SIRT1 or one of the other signals. In addition, Dr. Walsh will examine the effect of these genetic alterations on ischemia-induced angiogenesis in muscle and adipose tissue. Dr. Bhasin will examine the role of exercise in conjunction with androgen supplementation in synergistic activation of anabolic signaling in the rodent models of hypogonadism. The instrument will also be used to examine the basis for the beneficial effects of exercise in mice with metabolic heart disease and myocardial dysfunction (Colucci)~ the ability of testosterone to enhance exercise performance in mice as they age (Bhasin and Jasuja)~ and the effects of overexpression and knockout of the myokine myostatin on exercise performance ( Bhasin and Guo). In other investigations, Dr. Kandror will examine the mechanism by which exercise increases glucose uptake in the rodent cerebellum in vivo and Drs. Seldin and Jasuja will carry out studies of a mouse with genetic deletion of three of the four subunits of casein kinase 2. These mice are characterized by diminished body fat, increased food intake and body temperature and a decreased ability to exercise.In addition to its use for these studies, we anticipate the oxymax treadmill apparatus will more closely link the research of the investigators who use it, based on their common interests in both exercise and the signaling events that it produces.